Inhibitory anti-FLT3 antibodies are capable of mediating antibody-dependent cell-mediated cytotoxicity and reducing engraftment of acute myelogenous leukemia blasts in nonobese diabetic/severe combined immunodeficient mice

Obdulio Piloto, Mark J Levis, David Huso, Yiwen Li, Hongli Li, Mei Nai Wang, Rajiv Bassi, Paul Balderes, Dale L. Ludwig, Larry Witte, Zhenping Zhu, Daniel J. Hicklin, Donald Small

Research output: Contribution to journalArticle

Abstract

Aberrant FLT3 expression and/or mutation plays a significant role in leukemogenesis. This has prompted the development of selective small molecule tyrosine kinase inhibitors against FLT3. However, like most tyrosine kinase inhibitors, those against FLT3 are not completely specific and at the doses required to completely inhibit target, significant toxicities may occur. In addition, tyrosine kinase inhibitors for other kinases have been shown to select for cells that become resistant. To overcome some of these limitations we developed two fully human phage display monoclonal antibodies against FLT3 (IMC-EB10 and IMC-NC7). These antibodies inhibited ligand-mediated activation of wild-type FLT3 and constitutively activated mutant FLT3 and in most cell types affected downstream STAT5, AKT, and mitogen-activated protein kinase activation. In addition to interfering with FLT3 signaling, IMC-EB10 and, to a significantly lesser extent, IMC-NC7 initiated antibody-dependent cell-mediated cytotoxicity on FLT3-expressing cells. When IMC-EB10 was used in vivo to treat nonobese diabetic/severe combined immunodeficient mice given injections of primary FLT3/ITD acute myelogenous leukemia samples or myeloid cell lines with FLT3 expression, it significantly decreased engraftment of leukemic cells and increased survival, respectively. In contrast, IMC-EB10 treatment did not reduce engraftment of normal human CB34+ cord blood cells nor did it show any significant inhibition of normal murine hematopoiesis. Thus, these types of antibodies have the potential to be safe and effective new therapeutic agents for acute myelogenous leukemia and possibly other FLT3-expressing malignancies.

Original languageEnglish (US)
Pages (from-to)1514-1522
Number of pages9
JournalCancer Research
Volume65
Issue number4
DOIs
StatePublished - Feb 15 2005

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Antibody-Dependent Cell Cytotoxicity
SCID Mice
Acute Myeloid Leukemia
Anti-Idiotypic Antibodies
Protein-Tyrosine Kinases
Antibodies
Hematopoiesis
Myeloid Cells
Mitogen-Activated Protein Kinases
Fetal Blood
Bacteriophages
Blood Cells
Cell Survival
Phosphotransferases
Monoclonal Antibodies
Ligands
Cell Line
Mutation
Injections
IMC-EB10

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Inhibitory anti-FLT3 antibodies are capable of mediating antibody-dependent cell-mediated cytotoxicity and reducing engraftment of acute myelogenous leukemia blasts in nonobese diabetic/severe combined immunodeficient mice. / Piloto, Obdulio; Levis, Mark J; Huso, David; Li, Yiwen; Li, Hongli; Wang, Mei Nai; Bassi, Rajiv; Balderes, Paul; Ludwig, Dale L.; Witte, Larry; Zhu, Zhenping; Hicklin, Daniel J.; Small, Donald.

In: Cancer Research, Vol. 65, No. 4, 15.02.2005, p. 1514-1522.

Research output: Contribution to journalArticle

Piloto, Obdulio ; Levis, Mark J ; Huso, David ; Li, Yiwen ; Li, Hongli ; Wang, Mei Nai ; Bassi, Rajiv ; Balderes, Paul ; Ludwig, Dale L. ; Witte, Larry ; Zhu, Zhenping ; Hicklin, Daniel J. ; Small, Donald. / Inhibitory anti-FLT3 antibodies are capable of mediating antibody-dependent cell-mediated cytotoxicity and reducing engraftment of acute myelogenous leukemia blasts in nonobese diabetic/severe combined immunodeficient mice. In: Cancer Research. 2005 ; Vol. 65, No. 4. pp. 1514-1522.
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abstract = "Aberrant FLT3 expression and/or mutation plays a significant role in leukemogenesis. This has prompted the development of selective small molecule tyrosine kinase inhibitors against FLT3. However, like most tyrosine kinase inhibitors, those against FLT3 are not completely specific and at the doses required to completely inhibit target, significant toxicities may occur. In addition, tyrosine kinase inhibitors for other kinases have been shown to select for cells that become resistant. To overcome some of these limitations we developed two fully human phage display monoclonal antibodies against FLT3 (IMC-EB10 and IMC-NC7). These antibodies inhibited ligand-mediated activation of wild-type FLT3 and constitutively activated mutant FLT3 and in most cell types affected downstream STAT5, AKT, and mitogen-activated protein kinase activation. In addition to interfering with FLT3 signaling, IMC-EB10 and, to a significantly lesser extent, IMC-NC7 initiated antibody-dependent cell-mediated cytotoxicity on FLT3-expressing cells. When IMC-EB10 was used in vivo to treat nonobese diabetic/severe combined immunodeficient mice given injections of primary FLT3/ITD acute myelogenous leukemia samples or myeloid cell lines with FLT3 expression, it significantly decreased engraftment of leukemic cells and increased survival, respectively. In contrast, IMC-EB10 treatment did not reduce engraftment of normal human CB34+ cord blood cells nor did it show any significant inhibition of normal murine hematopoiesis. Thus, these types of antibodies have the potential to be safe and effective new therapeutic agents for acute myelogenous leukemia and possibly other FLT3-expressing malignancies.",
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T1 - Inhibitory anti-FLT3 antibodies are capable of mediating antibody-dependent cell-mediated cytotoxicity and reducing engraftment of acute myelogenous leukemia blasts in nonobese diabetic/severe combined immunodeficient mice

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AU - Levis, Mark J

AU - Huso, David

AU - Li, Yiwen

AU - Li, Hongli

AU - Wang, Mei Nai

AU - Bassi, Rajiv

AU - Balderes, Paul

AU - Ludwig, Dale L.

AU - Witte, Larry

AU - Zhu, Zhenping

AU - Hicklin, Daniel J.

AU - Small, Donald

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AB - Aberrant FLT3 expression and/or mutation plays a significant role in leukemogenesis. This has prompted the development of selective small molecule tyrosine kinase inhibitors against FLT3. However, like most tyrosine kinase inhibitors, those against FLT3 are not completely specific and at the doses required to completely inhibit target, significant toxicities may occur. In addition, tyrosine kinase inhibitors for other kinases have been shown to select for cells that become resistant. To overcome some of these limitations we developed two fully human phage display monoclonal antibodies against FLT3 (IMC-EB10 and IMC-NC7). These antibodies inhibited ligand-mediated activation of wild-type FLT3 and constitutively activated mutant FLT3 and in most cell types affected downstream STAT5, AKT, and mitogen-activated protein kinase activation. In addition to interfering with FLT3 signaling, IMC-EB10 and, to a significantly lesser extent, IMC-NC7 initiated antibody-dependent cell-mediated cytotoxicity on FLT3-expressing cells. When IMC-EB10 was used in vivo to treat nonobese diabetic/severe combined immunodeficient mice given injections of primary FLT3/ITD acute myelogenous leukemia samples or myeloid cell lines with FLT3 expression, it significantly decreased engraftment of leukemic cells and increased survival, respectively. In contrast, IMC-EB10 treatment did not reduce engraftment of normal human CB34+ cord blood cells nor did it show any significant inhibition of normal murine hematopoiesis. Thus, these types of antibodies have the potential to be safe and effective new therapeutic agents for acute myelogenous leukemia and possibly other FLT3-expressing malignancies.

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